Experiencing an emotionally traumatic event, even without physical injury, results in developing a debilitating condition, termed Post-Traumatic Stress Disorder (PTSD) in an estimated 20-30% of people, including the over 2 million US military personnel deployed in guerilla-type warfare (Operations Enduring Freedom and Iraqi Freedom) which is characterized with high level of unpredictable and recurring exposure to traumatic events. Thus, it is not surprising that PTSD inflicts rising costs to the Veteran?s Administration and society, in general, due to loss of productivity and quality of life. The VA costs associated with paying PTSD-related disability have been steadily rising since 1999, reaching over $2 billion in treatment costs (2004-2009), plus nearly 5 billion in disability payments. Considering that 80% continue to require treatment past 3 years after diagnosis, it is clear that decreasing the number of veterans requiring treatment for PTSD would decrease VA costs associated with this disorder, and, importantly, increase the quality of life for many veterans. A previous history of PTSD or other anxiety disorders renders some people more susceptible to developing PTSD after subsequent traumatic events. Thus, veterans treated for PTSD, or with PTSD susceptibility, are more likely to develop PTSD when they experience non-combat trauma, such as auto accidents, assault, and natural disasters. Therefore, identifying susceptibility and ways to prevent it could decrease PTSD-associated VA costs. Understanding the susceptibility factors for developing PTSD can help reduce the probability of occurrence after experiencing emotional trauma. The goal of this grant is to build upon our recent discovery of susceptibility and sequelae factors of emotional trauma. We propose to investigate whether an elevated pro-inflammatory profile is a susceptibility factor and whether it contributes to the disrupted function of the medial prefrontal cortex (mPFC) and hippocampus before emotional trauma (Aim 1) that we have already identified. In Aim 2, we propose to investigate whether decreasing the pro- inflammatory state in susceptible rats will increase their resilience, measured by their post-trauma behavior and functional activation of the mPFC and hippocampus. For the proposed studies, we will combine two indispensable tools: 1) RISP: our behavioral rat model for revealing individual susceptibility to a PTSD-like phenotype before experiencing emotional trauma (fear conditioning). This phenotype includes: impaired fear extinction, lasting elevated startle response and generalized anxiety-like behavior. 2) Arc/Homer 1a catFISH method: the sensitive cellular imaging method, co- developed by the PI, which can assess both size and overlap of neuronal ensembles engaged in plasticity after two distinct behavioral events. The findings from this research have the potential to revolutionize the assessment of susceptibility to PTSD-like behaviors and suggest new ways to build resilience.